LT Cell biology, immunology and host defense of the
lungs
Epithelial cells are the first target in the lung of inhaled substances
Trachea/bronchus bronchi non-respiratory bronchioles respiratory bronchioles
alveolar ducts alveoli (+ capillaries)
Epithelium consists of club cells, ciliated cells, goblet cells (mucus production) and basal cells
(progenitor cells)
Closer to the alveoli, there’re less goblet and basal cells
The alveoli (in the parenchyma) can be divided in alveolar type 1 and 2 cells; type 1 cells are
very thin, and diffusion takes place here; type 2 cells are the progenitor cells, and they
produce surfactant
The immune defense consists of resident cells and cells that are recruited during an infection
Several layers of respiratory host defense:
- Mechanical barrier (epithelium); adherens junctions and tight junctions keep a closed
barrier between the epithelial cells
- Ciliary action and mucus production (= mucociliary clearance); when it’s not working,
you cough to help to get rid of the stuff; the ciliary move at a certain frequency
- Production of cytokines and chemokines when the epithelium is triggered; released
into the lumen and blood
- Transport antibodies (IgE) from inside (blood) to outside (lumen of lungs); leads to
opsonization and neutralization (so the bacteria don’t reach the epithelium); done by
the receptor pIgR
- Production of endogenous antibiotics (body’s own antimicrobial peptides and
proteins); expressed by a variety of cells including epithelia and immune cells;
expression is constitutively or induced; antibacterial, antifungal, antiviral and
antiparasitic; depending on their levels, they’re pro-inflammatory or anti-
inflammatory, the same for anticancer activity; the antibiotics can modulate the
activity of immune cells, recruit immune cells or directly kill pathogen (lysis or
internal targets)
There’s also microbiota that live in the lung (like in the GI tract); but it is still unknown
whether it has a purpose or whether it just happens because you breathe in the air
containing bacteria
There’s a difference in the distribution of the microbiota throughout the lung due to
differences in pH, pO2, pCO2, temperature, etc.
COPD is a lung disease characterized by chronic inflammation, leading to tissue destruction
and a progressive decline in lung function
Main risks are cigarette smoking and air pollution
There’s more mucus production, but less ciliary activity, leading to much coughing; besides,
the diffusion surface is decreased; there’s remodeling of the lung epithelium (mucous
metaplasia and less ciliary cells)
The patients are vulnerable for infectious diseases (causing more damage)
Basal cells can differentiate in vitro creating a differentiated epithelium in vitro; this can be
used for research
, The electrical resistance is a measure for epithelial barrier function
Another way to measure the epithelial function is analyzing the microbial expression or
analyzing the transport of antibodies through the epithelium (pIgR activity)
LT Lung cancer and immunotherapy
Lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer
(SCLC); NSCLC is divided into adenocarcinoma, squamous cell carcinoma and large cell
carcinoma
SCLC is more aggressive than NSCLC; treated with radiation therapy and chemotherapy
50% of the NSCLC patients present with uncurable metastatic disease; treatment includes
surgery, chemotherapy, radiotherapy, targeted therapy (targeted at the mutation) and
immunotherapy
Intrinsic tumor suppression senescence and apoptosis act as barrier against further
development of any neoplastic cell
Extrinsic tumor suppressor mechanisms provide further protection dependence on
appropriate signals from micro-environment, prevention of cell cycle progression in face of
dysregulated junctional processes (cell polarity), limitation of transformation to tumor cell
The immune system protects the lungs from cancer by:
- Protecting the host form virus-induced tumors by eliminating viral infections
- Clearing inflammation (which is an environment that promotes tumorigenesis)
- Cancer immunosurveillance (elimination of tumor cells on basis of expression of
tumor-specific antigens)
The immune reaction can be in 3 phases elimination of the tumor, equilibrium (stable
situation, tumor is controlled) or escape of the immune system by the tumor
When the antigens are lost, the equilibrium phase shifts to the escape phase
The immune reaction involves release of cancer antigens, presentation of these antigens by
APCs and dendritic cells, activation of T cells, trafficking of T cells, infiltration of T cells into
the tumor, recognition of the tumor by T cells and killing of the cancer cells
Mechanisms of escape (immunoediting):
- Reduced immune recognition by loss of HLA class I molecules less recognition by
CD8 cytotoxic cells (but more recognition by NK cells)
- Increase resistance to attack by immune cells by increased expression of STAT3
(promotes proliferation and anti-apoptotic) and BCL-2 (anti-apoptotic)
- Development of immunosuppressive microenvironment by expression of cytokines
(VEGF, IL-10, TGF-b) and immunoregulatory molecules (checkpoint molecules) and by
infiltration of regulatory T cells and myeloid derived suppressor cells
Checkpoint molecules are e.g., PD-L1, CTLA4, TIGIT; high expression of these molecules
prevents apoptosis; these molecules can be used for targeted therapy antibodies that
block the function of these molecules; for example, nivolumab which is IgG4 directed against
PD-1
Radiotherapy has the potential to induce stress responses and cell death in cancer cells and
thus drives dendritic cell-T cell interaction, but may also drive recruitment of innate immune
cells with tumor promoting potential
